In 1978, it was reported for the first time that an antisense oligonucleotide (antisense molecule) inhibited infection by influenza virus. Reports followed that antisense oligonucleotides also inhibited oncogene expression and AIDS infection. Since antisense oligonucleotides specifically control the expression of untoward genes, they are one of the fields that have been expected most in recent years.
The antisense method is based on the concept that the flow of information in the so-called central dogma, i.e., DNA→mRNA→protein, is to be controlled using an antisense oligonucleotide.
However, if a natural DNA or RNA oligonucleotide was applied as an antisense molecule to this method, the problem arose that it was hydrolyzed by an in vivo enzyme, or its cell membrane permeation was not high. To resolve such problems, numerous nucleic acid derivative were synthesized, and extensively studied. For example, phosphorothioates having an oxygen atom on the phosphorus atom substituted by a sulfur atom, and methyl phosphonates having a methyl group as a substituent were synthesized. Recently, products having the phosphorus atom also substituted by a carbon atom, or molecules having a ribose converted into an acyclic skeleton form have been synthesized (F. Eckstein et al., Biochem., 18, 592(1979); P. S. Miller et al., Nucleic Acids Res., 11, 5189(1983); P. Herdewijn et al., J. Chem. Soc. Perkin Trans. 1, 1567(1993); P. E. Nielsen et al., Science, 254, 1497(1991)); C. A. Stein and A. M. Krieg (ed) “Applied Antisense Oligonucleotide Technology,” Willy-Liss (1998); and J. J. Toulme et al., Prog. Nucl. Acid Rev. Mol. Biol., 67, 1(2001)).
However, none of the artificial oligonucleotides have obtained nucleoside and oligonucleotide analogues fully satisfactory in terms of a duplex-forming capacity with single-stranded RNA and DNA, a triplex-forming capacity with double-stranded DNA, in vivo stability, or ease of synthesis of oligonucleotides.